PROJECT SUMMARY/ABSTRACT Project Summary - The peptide hormone insulin stimulates the uptake and storage of glucose and other nutrients into adipose tissue and skeletal muscle while simultaneously repressing glucose efflux from the liver. Insulin resistance occurs when a normal dose of the hormone is incapable of eliciting these anabolic responses, and the condition is a risk factor for cardiovascular disease, type 2 diabetes, and certain forms of cancer. Pathogenic factors implicated in the onset of insulin resistance (e.g. saturated fatty acids, tumor necrosis factor-alpha, and glucocorticoids) have been shown to selectively induce the synthesis of ceramide, a sphingolipid that has been shown to antagonize insulin action. We present findings indicating that the inhibition of ceramide synthesis in rodents ameliorates insulin resistance caused by saturated fats, glucocorticoids, and obesity. Moreover, we include preliminary data identifying the liver as a likely target of ceramide action, that white adipocytes secrete ceramide, and that ceramide levels within the portal circulation are markedly elevated during times of metabolic stress. Because of these data, we hypothesize that ceramide generated in and secreted from visceral adipose tissue modulates insulin sensitivity and glucose homeostasis in the liver as a physiological mechanism for communicating nutrient status or energy need. To test the role of this enterohepatic axis in the regulation of peripheral insulin sensitivity, we will complete the following aims: first, we will identify the primary tissues that produce the pools of ceramide which impaig glucose tolerance; second, we will investigate the role of factors implcated in insulin resistance (e.g. tumor necrosis factor-alpha, glucocorticoids) in the modulation of ceramide synthesis; and third, we will elucidate the mechanism underyling ceramide's induction of hepatic insulin resistance. Collectively, these studies could uncover a novel regulatory axis that modulates peripheral insulin sensitivity and energy utilization during times of feast, famine, or stress. Project Description Page 6 Principal Investigator/Program Director (Last, first, middle): Summers, Scott, A.